Transplantation of PC1/3-Expressing alpha-cells improves glucose handling and cold tolerance in leptin-resistant mice.
Type 2 diabetes (T2D) is characterized by elevated blood glucose levels owing to insufficient secretion and/or activity of the glucose-lowering hormone insulin. Glucagon-like peptide-1 (GLP-1) has received much attention as a new treatment for diabetes because of its multiple blood glucose-lowering effects, including glucose-dependent enhancement of insulin secretion, inhibition of gastric emptying, and promotion of the survival and growth of insulin-producing beta-cells. GLP-1, along with GLP-2 and oxyntomodulin, is produced in the intestinal L-cell via processing of proglucagon by prohormone convertase 1/3 (PC1/3), while in the pancreatic alpha-cell, coexpression of proglucagon and the alternate enzyme PC2 typically results in differential processing of proglucagon to yield glucagon. We used alginate-encapsulated alpha-cells as a model to evaluate continuous delivery of PC1/3- or PC2-derived proglucagon products. In high fat-fed and db/db mice, PC1/3-, but not PC2-expressing alpha-cells improved glucose handling and transiently lowered fasting glucose levels, suggesting that continuous delivery of PC1/3-derived proglucagon products via cell therapy may be useful for diabetes treatment. In addition, we show that long-term treatment with PC1/3-expressing, but not PC2-expressing, alpha-cells improved cold-induced thermogenesis in db/db mice, demonstrating a previously unappreciated effect of one or more PC1/3-derived alpha-cell products.
Wideman
Rhonda D
RD
Laboratory of Molecular and Cellular Medicine, Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada.
Gray
Sarah L
SL
Covey
Scott D
SD
Webb
Gene C
GC
Kieffer
Timothy J
TJ
D000818:Animals; D001823:Body Composition; D002478:Cells, Cultured; D003080:Cold Temperature; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000628:therapy; D005934:Glucagon / Q000378:metabolism; D050416:Glucagon-Secreting Cells / Q000378:metabolism* / Q000637:transplantation*; D005947:Glucose / Q000378:metabolism*; D020738:Leptin / Q000494:pharmacology; D051379:Mice; D052336:Proglucagon / Q000378:metabolism; D045664:Proprotein Convertase 1 / Q000378:metabolism*; D045706:Proprotein Convertase 2 / Q000378:metabolism
D020738:Leptin; D052336:Proglucagon; D005934:Glucagon; D045664:Proprotein Convertase 1; D045706:Proprotein Convertase 2; D005947:Glucose